This application is the national phase of international application PCT/GB99/00335 filed Feb. 2, 1999 which designated the U.S.
The present invention relates to pharmaceutical compositions which comprise anti-inflammatory and immunomodulatory compounds that act via antagonism of the CCR2 receptor, (also known as the MCP-1 receptor), leading inter alia to inhibition of Monocyte Chemoattractant Protein-1 (MCP-1). These compounds contain a bicyclic aromatic moiety. The invention further relates to novel compounds for use in the compositions, to processes for their preparation. to intermediates useful in their preparation and to their use as therapeutic agents.
MCP-1 is a member of the chemokine family of pro-inflammatory proteins which mediate leukocyte chemotaxis and activation. MCP-1 is a Cxe2x80x94C chemokine which is one of the most potent and selective T-cell and monocyte chemoattractant and activating agents known. MCP-1 has been implicated in the pathophysiology of a large number of inflammatory diseases including rheumatoid arthritis, glomerular nephritides, lung fibrosis, restenosis (International Patent Application WO 94/09128), alveolitis (Jones et al., 1992, J. Immunol., 149, 2147) and asthma. Other disease areas where MCP-1 is thought to play a part in their pathology are atherosclerosis (e.g. Koch et al., 1992, J. Clin. Invest., 90, 772 -779), psoriasis (Deleuran et al., 1996, J. Dermatological Science, 13,. 228-236), delayed-type hypersensitivity reactions of the skin, inflammatory bowel disease (Grimm et al., 1996, J. Leukocyte Biol., 59,. 804-812), multiple sclerosis and brain trauma (Berman et al, 1996, J. Immunol., 156,. 3017-3023). An MCP-1 inhibitor may also be useful to treat stroke, reperfusion injury, ischemia, myocardial infarction and transplant rejection.
MCP-1 acts through the CCR2 receptor. MCP-2 and MCP-3 may also act, at least in part, through this receptor. Therefore in this specification, when reference is made to xe2x80x9cinhibition or antagonism of MCP-1xe2x80x9d or xe2x80x9cMCP-1 mediated effectsxe2x80x9d this includes inhibition or antagonism of MCP2 and/or MCP-3 mediated effects when MCP-2 and/or MCP-3 are acting through the CCR2 receptor.
WO-9631492 describes a range of compounds including bicyclic compounds which are inhibitors of endothelin receptors. JP-3284177 discloses the preparation of certain formyl substituted pyrrolo-pyrroles for use in a range of applications. In addition, U.S. Pat. No.4,751,231 describes the preparation of substituted thienosulphonamides as antiglaucoma agents.
The applicants have found a class of compounds containing a bicyclic moiety which have useful inhibitory activity against MCP-1.
The present invention provides a pharmaceutical composition comprising a compound of formula (I): 
or a pharmaceutically acceptable salt or esters of amides thereof, which is an inhibitor of monocyte chemoattractant protein- I and wherein A and B together with the carbon atoms to which they are attached, form an optionally substituted 5 membered aromatic ring which includes at least one heteroatom;
X is CH2 or SO2;
R1 is an optionally substituted aryl or heteroaryl ring;
R2 is carboxy, cyano, xe2x80x94C(O)CH2OH, xe2x80x94CONHR4, xe2x80x94SO2NHR5, tetrazol-5-yl, SO3H, or a group of formula (VI): 
xe2x80x83where R4 is selected from hydrogen, alkyl, aryl, cyano, hydroxy, xe2x80x94SO2R9 where R9 is alkyl, aryl, heteroaryl, or haloalkyl, or R4 is a group-(CHR10)rxe2x80x94COOH where r is an integer of 1-3 and each R10 group is independently selected from hydrogen or alkyl; R5 is alkyl, optionally substituted aryl such as optionally substituted phenyl or optionally substituted heteroaryl such as 5 or 6 membered heteroaryl groups, or a group COR6 where R6 is hydrogen, alkyl, aryl, heteroaryl or haloalkyl; R7 and R8 are independently selected from hydrogen or alkyl, particularly C1-4 alkyl; and
R3 is hydrogen, a functional group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted cycloalkyl; in combination with a pharmaceutically acceptable carrier or diluent.
Suitably the composition comprises a compound of formula (I) or a salt or in vivo hydrolysable ester thereof.
Compounds of formula (I) are inhibitors of monocyte chemoattractant protein-1. In addition, they appear to inhibit RANTES induced chemotaxis. RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted) is another chemokine from the same family as MCP-1, with a similar biological profile, but acting though the CCR1 receptor. As a result, these compounds can be used to treat disease mediated by these agents, in particular inflammatory disease.
Example of such compounds are compounds where A, B, X, R1 and R3 are as defined above, and where R2 is as defined above but R4 is selected from cyano, hydroxy, xe2x80x94SO2R9 where R9 is alkyl, aryl, hcteroaryl, or haloalkyl, or R4 is a group-(CHR10)rxe2x80x94COOH where r is an integer of 1-3 and each R10 group is independently selected from hydrogen or alkyl; R5 is optionally substituted phenyl or optionally heteroaryl groups, or a group COR6 where R6 is alkyl, aryl, heteroaryl or haloalkyl; R7 and R8 are independently selected from hydrogen or alkyl, particularly C1-4 alkyl.
In this specification the term xe2x80x9cheteroatomxe2x80x9d refers to non-carbon atoms such as oxygen, nitrogen or sulphur atoms. The term xe2x80x98alkylxe2x80x99 when used either alone or as a suffix includes straight chain and branched structures. These groups may contain up to 10, preferably up to 6 and more preferably up to 4 carbon atoms. Similarly the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to unsaturated straight or branched structures containing for example from 2 to 10, preferably from 2 to 6 carbon atoms. Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynyl are similar in nature but have at least 3 carbon atoms. Terms such as xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkanoylxe2x80x9d comprise alkyl moieties as defined above, attached to the appropriate functionality.
The term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo. References to aryl groups include aromatic carbocylic groups such as phenyl and naphthyl. The term xe2x80x9cheterocyclylxe2x80x9d includes aromatic or non-aromatic rings, for example containing from 4 to 20, suitably from 5 to 10 ring atoms, at least one of which is a heteroatom such as oxygen, sulphur or nitrogen. Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, iosquinolinyl, quinoxalinyl, benzthiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
xe2x80x9cHeteroarylxe2x80x9d refers to those groups described above which have an aromatic character. The term xe2x80x9caralkylxe2x80x9d refers to aryl substituted alkyl groups such as benzyl.
Other expressions used in the specification include xe2x80x9chydrocarbylxe2x80x9d which refers to any structure comprising carbon and hydrogen atoms. For example, these may be alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl.
The term xe2x80x9cfunctional groupxe2x80x9d refers to reactive substituents. They may comprise electron-donating or electron-withdrawing. Examples of such groups include halo, cyano, nitro, C(O)nR11, OR11, S(O)mR11, NR12R12xe2x80x2, C(O)NR12R12xe2x80x2, OC(O)NR12R12xe2x80x2, xe2x80x94CHxe2x95x90NOR11, xe2x80x94NR12C(O)nR11, xe2x80x94NR11CONR12R12xe2x80x2, xe2x80x94Nxe2x95x90CR12R12xe2x80x2, S(O)mNR12R12xe2x80x2 or xe2x80x94NR12S(O)mR11 where R11, R12 and R12xe2x80x2 are independently selected from hydrogen or optionally substituted hydrocarbyl, or R12 and R12xe2x80x2 together form an optionally substituted ring which optionally contains further heteroatoms such as S(O)m, oxygen and nitrogen, n is an integer of 1 or 2, m is 0 or an integer of 1-3. Where functional groups comprise S(O)mNR12R12xe2x80x2 or xe2x80x94NR12S(O)mR11, m is generally an integer from 1-3. For the avoidance of doubt, where R12 and R12xe2x80x2 together form an optionally substituted ring, the ring will comprise a non-aromatic heterocyclyl group as defined above.
Suitable optional substituents for hydrocarbyl groups R11, R12 and R12xe2x80x2 include halo, perhaloalkyl such as trifluoromethyl, mercapto, hydroxy, alkoxy, oxo, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, aryloxy (where the aryl group may be substituted by halo, nitro, or hydroxy), cyano, nitro, amino, mono- or di-alkyl amino, alkylamido, oximino (for example hydroxyimino or alkyloxyimino) or S(O)mRy where m is as defined above and Ry is alkyl.
Examples of optional substituents for the group A-B include functional groups as defined above or optionally substituted hydrocarbyl groups or optionally substituted heterocyclic groups. A particular substituent for the A-B group is a group of sub-formula (IV). 
Suitably A and B together with the carbon atoms to which they are attached form a 5 membered heteroaryl ring of any one of the sub-formulae: 
where R13, R14 and R15 are as independently selected from hydrogen or a substituent group.
Suitably substituents R13, R14, R15 include functional groups as defined above or optionally substituted hydrocarbyl groups.
Suitable hydrocarbyl groups for R13, R14, R15 include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl.
Particular substituent groups for the A-B ring include trifluoromethyl; optionally substituted C1-4alkyl such as aralkyl, carboxyalkyl or the amide derivative thereof; halo; hydroxy; C1-4alkoxy; C1-4alkanoyl; C1-4alkanoyloxy; amino; cyano; C1-4alkylamino; di(C1-4alkyl)amino; C1-4alkanoylamino; nitro; carbamoyl; C1-4alkoxycarbonyl; thiol; C1-4alkylsulphanyl; C1-4alkylsulphinyl; C1-4alkylsulphonyl; sulphonamido or alkyl or aryl sulphonamido, carbamoyIC1-4alkyl; Nxe2x80x94(C1-4alkyl)carbamoylC1-4alkyl; Nxe2x80x94(C1-4alkyl)2carbamoyl-C1-4alkyl; hydroxyC1-4alkyl; C1-4alkoxyC1-4alkyl; mono-or di-alkyl or aryl substituted urea; morpholino; thiomorpholino; oxythiomorpholino; pyrrolidinyl; carboxyC1-4alkylamino; R16, xe2x80x94NHR17 and xe2x80x94OR17 (where R16 and R17 are independently selected from optionally substituted phenyl and an optionally substituted 5- or 6-membered heteroaryl ring). Suitable optional substituents for R16 and R17 include those listed above for R11, R12 or R12xe2x80x2. Suitable optional substituents for R16 and R17 also include those listed herein for R1. Alkyl or aryl sulphonamido substituents may themselves be optionally substituted, for example by substituents listed above for R11, R12 or R12xe2x80x2 or listed herein for R1.
Examples of compounds of formula (I) are those where the ring A-B carries at least one substituent.
Suitably, when A-B forms a group of sub-formula (iii) above, and R15 is hydrogen, R14 is other than formyl, and/or R13 is other than hydrogen, alkyl or aralkyl.
Suitably, where A-B forms a group of sub-formula (v) above, R13 is other than an amidino group.
Substituents are suitably arranged at or close to the side of the ring designated xe2x80x9cAxe2x80x9d in preference to the xe2x80x9cBxe2x80x9d position. Thus, in compounds of subformulae (i) to (xviii) above, R13 and/ or R14 where present are suitably other than hydrogen, most preferably R13 is other than hydrogen. The positions closest to the xe2x80x9cBxe2x80x9d position are preferably hydrogen. Therefore, in the above sub-formulae (i) to (xviii), R15 is most preferably hydrogen.
Preferred substituents for the A-B ring and therefore, preferred examples of R13, R14 and R15 include C1-4 alkyl, in particular methyl, which alkyl group is optionally substituted with hydroxy, amino or mono or di-C1-4 alkylamino such as methylamino or dimethylamino; cyano; halogen in particular bromine; thienyl; tetrazolyl; phenyl optionally substituted with amino; C1-4 alkoxy, in particular methoxy; carboxy or carboxamido.
Preferred substituents for the A-B ring where present and therefore, preferred examples of R13, R14 and R15 are C1-4alkyl, in particular methyl.
Suitable optional substituents for R1 in formula (I) include those listed above for R11, R12 and R12xe2x80x2 as well as alkyl, alkenyl, or alkynyl.
Suitable optional substituents for alkyl, alkenyl, alkynyl, groups R3 include those listed above for R11, R12 and R12xe2x80x2, and for aryl, aralkyl, cycloalkyl or heterocyclyl groups R3, the substituents may be as listed herein for R1.
Suitably X is CH2.
Suitably R1 is an optionally substituted phenyl, naphthyl, furyl, pyridyl or thienyl ring, and preferably a substituted phenyl or pyridyl ring.
Preferably R1 is substituted by at least one substituent, particularly when R1 is phenyl.
Particular substituents for R1 include trifluoromethyl, C1-4alkyl, halo, trifluoromethoxy, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkanoylamino, nitro, carboxy, carbamoyl, C1-4alkoxycarbonyl, thiol, C1-4alkylsulphanyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, sulphonamido, carbamoylC1-4alkyl, Nxe2x80x94(C1-4alkyl)carbamoylC1-4alkyl, Nxe2x80x94(C1-4alkyl)2carbamoyl-C1-4alkyl, hydroxyC1-4alkyl or C1-4alkoxyC1-4alkyl.
Additionally or alternatively, two such substituents together may form a divalent radical of the formula xe2x80x94O(CH2)1-4Oxe2x80x94 attached to adjacent carbon atoms on the R1 ring.
Preferred substituents for R1 are one or more non-polar substituents such as halo.
In particular, R1 is substituted by one or more halo groups, in particular chlorine. A particular example of an R1 group is 3,4-dichlorophenyl, 3,4difluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrid-5-yl.
Preferably, R1 is 3,4-dichlorophenyl.
Examples of groups R2 include carboxy, tetrazol-5-yl, cyano, SO3H, xe2x80x94SO2NHR5 xe2x80x94CONHR4, or a group of formula (VI). 
where R5 is as defined above, R7 and R8 are independently selected from hydrogen or alkyl, particularly C1-4 alkyl, R4 is cyano, OH, xe2x80x94SO2xe2x80x94C1-4alkyl (where the alkyl group is optionally substituted with halo such as fluoro, particularly at the alpha position), xe2x80x94SO2CF3, xe2x80x94SO2-pheny[, xe2x80x94(CHR10)rxe2x80x94COOH, where r is 1-3 and each R10 group is independently selected from hydrogen or alkyl such as C1-4 alkyl.
Preferably R2 is carboxy or a pharmaceutically acceptable salt or ester thereof, such as a C1-4 alkyl ester, and particularly carboxy or a pharmaceutically acceptable salt thereof, especially carboxy.
Suitable groups R3 include hydrogen, fluoro, chloro, bromo, iodo, methyl, cyano, trifluoromethyl, hydroxymethyl, alkoxyalkyl such as C1-4alkoxymethyl, methoxy, benzyloxy, carboxyalkoxy such as carboxymethoxy, methylsulphanyl, methylsulphinyl, methylsulphonyl or carboxyC3-6cycloalkyl, xe2x80x94(CHR21)rxe2x80x94NR22R23 (where r is 0-2, each R21 is independently hydrogen or alkyl, in particular C1-4 alkyl, R22 and R23 are independently selected from H and C1-4alkyl or R22 and R23 together with the nitrogen to which they are attached form a 5 or 6 membered ring optionally containing one further heteroatom selected from O, N, S, S(O) or SO2. Suitably R22 and R23 together form a heterocylic ring such as morpholino or piperazinyl.
Other such groups R3 include optionally substituted aryl groups, such as optionally substituted phenyl or naphthyl group. Suitable substituents for phenyl groups R3 include one or more groups selected from chlorine, fluorine, methyl, trifluoromethyl, trifluoromethoxy, amino, formyl, phenyl, methoxy, phenoxy or phenyl.
R3 may comprise a range of substituents as listed above, in particular, hydrogen or a small substituent group such as C1-4alkyl in particular methyl, or trifluoromethyl, and is preferably hydrogen.
Particularly suitable A-B groups are those of formula (i), (ii), (v) and (ix) as shown above. A further particularly suitable A-B group is that of formula (xi) above.
Particularly preferred compounds of formula (I) are compounds of formula (IA) or (IB): 
or a pharmaceutically acceptable salt, ester of amide thereof, where R1 is as defined above, and is preferably a halo substituted phenyl group such as 3,4-dichlorophenyl, R26 is hydrogen or C1-4 alkyl, in particular methyl, and in formula (IA)
(i) R24 is sulphur and R25 is CH; or
(ii) R24 is sulphur and R25 is nitrogen; or
(iii) R24 is oxygen and R25 is CH; or
(iv) R24 is NCH3 and R25 is CH;
and in Formula (IB)
(i) R24xe2x80x2 is CH and R25xe2x80x2 is sulphur; or
(ii) R24xe2x80x2 is CH and R25xe2x80x2 is oxygen; or
(iii) R24xe2x80x2 is nitrogen and R25xe2x80x2 is sulphur.
Particularly preferred examples are compounds of formula (IA) where R1 is a halo substituted phenyl such as 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro4-chlorophenyl, 3-chloro-4-fluorophenyl, R26 is hydrogen or methyl, R24 is sulphur and R25 is either CH or nitrogen.
Other particular examples are compounds of formula (IA) where R1 is a halo substituted phenyl such as 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro4-chlorophenyl, 3-chloro-4-fluorophenyl, R24 is oxygen, R25 is CH, and R26 is either hydrogen or methyl.
Yet further preferred examples are compounds of formula (IB) where R1 is a halo substituted phenyl such as 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, R25xe2x80x2 is sulphur, R26 is hydrogen and R24xe2x80x2 is either CH or nitrogen.
Preferably the compound of formula (IA) or (IB) is an acid.
Suitable pharmaceutically acceptable salts of compounds of formula (I) include are base salts such as an alkali metal salt for example sodium an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. In another aspect, where the compound is sufficiently basic, suitable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically acceptable salt is a sodium salt.
An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
Suitable pharmaceutically acceptable esters for carboxy include C1-6alkyl esters such as methyl or ethyl esters, C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxy-carbonyloxyC1-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and xcex1-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
A suitable value for an amide includes, for example, a Nxe2x80x94C1-6alkyl and N,N-di-(C1-6alkyl)amide such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethylamide.
Particular compounds of formula (I) are listed below in Table I. In the formula, the dotted line indicates the presence of a double bond, which is either between R40 and R41 or between R41 and R42 depending upon the nature and the valency of the groups R40, R41 and R42 as would be understood in the art.
Of these, the compounds numbered 4, 25, 34, 50 and 56 in Table I are of special interest and these compounds, or a pharmaceutically acceptable salt thereof, are provided as a further feature of the invention.
The invention further provides a compound of formula (I) as defined above for use in the treatment of inflammatory disease.
Furthermore, the invention provides the use of a compound of formula (I) as defined above in the preparation of a medicament for the treatment of inflammatory disease.
Certain compounds of formula I are know, for example particular compounds disclosed in Molecules (1997), 2(4), 69-79, Chem. Pap. (1996), 50(2), 72-76, Chem. Pap. (1994), 48(4), 268-73, Heterocycles (1994), 37(3), 1695-700 and (1989), 29(10), 1943-9, Coll. Czech. Chem. Commun. (1994), 59(2), 473-481 and 499-502, Coll. Czech. Chem. Commun. (1993), 58(9), 2139-49, Coll. Czech. Chem. Comm. (1992), 57(7), 1487-94, Monatsh. Chem. (1992), 123(8-9), 807-15 and Magn. Reson. Chem. (1990), 28(9), 830-1. However, prior to the present invention it was not known that any of these compounds possessed inhibitory activity against MCP-1.
Certain compounds of formula (I) are novel and these form a further aspect of the invention. Thus the invention farther provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. which is an inhibitor of monocyte chemoattractant protein-1; subject to the following provisos: a) that where A-B forms a group of sub-formula (i) or (iv) above, R1 is other than phenyl, amino phenyl or nitrophenyl; and b) that where A-B forms a group of sub-formula (iii) above, R13 is methyl and R15 is hydrogen, R14 is not CHO; c) that where A-B form a group of sub-formula (v) above and X is SO2, R1 is other than unsubstituted phenyl.
Particular and preferred novel compounds of formula (I) are those as described above in relation to the pharmaceutical compositions.
In particular a preferred group of compounds are compounds of formula (IA) and (IB) as defined above.
Some compounds of formula (I) may possess chiral centres. It is to be understood that the invention encompasses all such optical isomers and diasteroisomers of compounds of formula (I) and pharmaceutical compositions containing these.
The invention further relates to all tautomeric forms of the Compounds of formula (I) and pharmaceutical compositions containing these.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms and pharmaceutical compositions containing these.
Compounds of formula (I) are suitably prepared by reacting a compound of formula (VII): 
where A. B and R3 are as defined in relation to formula (I) and R27 is either hydrogen or a group R2 as defined in claim 1; with compound of formula (VIII):
R1xe2x80x94Xxe2x80x94Zxe2x80x83xe2x80x83VIII
where R1 and X are as defined in relation to formula (I) and Z is a leaving group; and thereafter if desired or necessary, converting the group R27 to a group R2 and/or to a different such group.
Suitable leaving groups for Z include halide such as chloride, bromide or iodide, as well as mesylate or tosylate. The reaction is suitably effected in an organic solvent such as dimethylformamide (DMF) tetrahydrofuran (THF) or DCM in the presence of a base such as sodium hydride, sodium hydroxide, potassium carbonate. Optionally the reaction is effected in the presence of a suitable phase transfer catalyst. The choice of base and solvent is interdependent to a certain extent in that certain solvents are compatible with some bases only as is understood in the art. For example, sodium hydride may preferably be used with dimethylformamide or tetrahydrofuran and sodium hydroxide is preferably used with dichloromethane and a phase transfer catalyst.
The reaction can be carried out at moderate temperatures, for example from 0 to 50xc2x0 C. and conveniently at about ambient temperature.
Preferably, R27 is an ester group in the compound of formula VII and this may be subsequently converted to an acid or amide or to another ester or salt, by conventional methods, For example, when X is a group SO2 and R2 is a methyl ester of carboxy, it may be converted to the corresponding carboxylic acid by reaction with lithium iodide in dry pyridine or DMF.
Alternatively, where R27 is hydrogen, it may be converted to for instance a carboxylic acid ester group by reaction with lithium diisopropyl amide (LDA), followed by an alkyl chloroformate. The reaction is suitably effected in an organic solvent such as tetrahydrofuran (THF) at low temperatures for example of from xe2x88x9278 to 0xc2x0 C., preferably at about xe2x88x9220 to xe2x88x9240xc2x0 C. In this case, the group on the nitrogen atom is suitably one that will direct metallation to the 2-position, such as phenylsulphonyl.
Compounds of formula (VII) are either known compounds or they may be prepared from known compounds by conventional methods.
For example. compounds of formula (VII) may be prepared by cyclisation of a compound of formula (IX): 
where A and B are as defined in relation to formula (I) and R28 and R29 represent a combination of moieties which can cyclise to form an appropriately substituted pyrrole ring. For example, one of R28 and R29 can be a group of formula xe2x80x94CHxe2x95x90C(R30)N3 where R30 is a group R2 as defined above, or a protected form thereof, and the other may be hydrogen. Cyclisation to form a compound of formula (VII) may then be effected by heating for example under reflux in an organic solvent, in particular a high boiling aprotic solvent such as xylene or toluene.
Alternatively, one of R28 and R29 may be nitro and the other may be a group of formula xe2x80x94CH2C(O)R27 where R27 is as defined above in relation to formula (VII). These compounds will cyclise in the presence of a catalyst such as palladium on carbon in the presence of hydrogen. The reaction may be effected at moderate temperatures for example of from 0 to 80xc2x0 C., conveniently at about ambient temperature.
Thus examples of compounds of formula (IX) include compounds of formula (X) and (XI): 
Compounds of formula (X) may be prepared for example by reacting a compound of formula (XII): 
with a compound of formula (XIII): 
where A, B, R3 and R27 are as defined hereinbefore. The reaction may be effected in an organic solvent such as ethanol at low temperatures of from xe2x88x9220 to 0xc2x0 C., suitably at about 0xc2x0 C. The reaction is suitably effected in the presence of a base such as an alkoxide, in particular an ethoxide, for example potassium ethoxide.
Compounds of formula (XIII) are suitably prepared by reacting a compound of formula (XIV): 
where R3 and R27 are as defined above and R30 is a leaving group such as halide and in particular bromide, with an azide salt, such as an alkali metal azide salt in particular sodium azide.
Compounds of formula (XI) may be prepared by reacting a compound of formula (XV): 
where A, B and R3 are as defined above, with a compound of formula (XVI): 
where R27 is as defined above and R31 leaving group. Examples of compounds of formula (XVI) are oxalates such as diethyloxalate. The reaction is suitably effected in the presence of a base such as sodium hydride in an organic solvent such as THF. Moderate temperatures of from 0 to 40 and conveniently ambient temperature is employed.
Compounds of formulae (XII),(XIV), (XV) and (XVI) are known compounds or they can be prepared from known compounds by conventional methods.
Substituents on the ring formed by A-B may be introduced either during synthesis as outlined above or using various methods which would be apparent to the skilled person depending upon the nature of the particular substituent to be introduced. Alternatively, one substituent may be changed for a different substituent using conventional chemical methods. Other possibilities would be apparent to the skilled person.
Certain of the intermediates defined herein are novel, for example certain compounds of formula (VII), and are provided as a further feature of the invention.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal track, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such an peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gun acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol. or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30xcexc or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on Formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the Formula I are useful in treating diseases or medical conditions which are due alone or in part to the effects of famesylation of rats.
In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however preferred.
In a further aspect, the invention provides a method of treating inflammatory disease by administering a compound of formula (I) as described above, or a pharmaceutical composition as described above,